4-(1,2,5,6-Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines and 4-(hexahydro-1-alkyl-3-pyridinyl)-2-thiazolamines having anti-psychotic activity

ABSTRACT

A unique series of 4-(1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines and 4-(hexahydro-1-alkyl-pyridinyl)-2-thiazolamines are disclosed. These compounds are useful as dopaminergic agents. Intermediates for preparing the compounds, pharmaceutical compositions containing them, and methods for using the pharmaceutical compositions for treating human psychosis, elevated blood pressure, Parkinson&#39;s disease, hyperprolactinaemia, sexual disorders, and acromegaly are described.

BACKGROUND OF THE INVENTION

The compounds of the instant invention are a unique series of4-(1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines and4-(hexahydro-1-alkyl-3-pyridinyl)-2-thiazolamines which are useful asdopaminergic agents, antipsychotics, and antihypertensives.

European patent application No. 117,082 discloses 4,5-disubstitutedthiazole derivatives having cardiotonic and antiulcer activity.

Japanese Kakai No. 58/035186 discloses certain dicarboxyaminothiazolederivatives having certain immunocontrolling power.

West German application No. 3247118A discloses substituted1,4-dihydropyridine derivatives with cardiovascular and antagonisticproperties.

SUMMARY OF THE INVENTION

One aspect of the present invention is a compound of the formula##STR1## wherein signifies the presence of a single or double bondbetween two carbon atoms; R is H or a straight or branched alkyl of fromone to four carbon atoms; R' is H, a straight or branched alkyl of fromone to four carbon atoms, or CO--R'" where R'" is a straight or branchedalkyl of from one to four carbon atoms; R" is a straight or branchedalkyl group of from one to eight carbon atoms, a straight or branchedalkenyl group of from two to eight carbon atoms, an aralkyl groupwherein the alkyl is straight or branched of from one to four carbonatoms, or a group of the formula --(CH₂)_(n) --O--(CH₂)_(m) --CH₃wherein n and m are each independently zero to four, or apharmaceutically acceptable acid addition salt thereof, or thestereoisomers thereof when is a single bond.

Another aspect of the present invention is a method of preparing acompound of Formula III which comprises:

(a) treating a pyridinyl-thiazolamine with an organic halide to productthe corresponding 1-substituted pyridinium salt;

(b) reducing selectively the salt to form the corresponding1,2,5,6-tetrahydropyridinylthiazolamine, and if desired;

(c) treating this thiazolamine with an acid anhydride to form anN-substituted acid amide: and

(d) converting the product of step b or c, if desired, to apharmaceutica-ly acceptable acid addition salt.

A third aspect of the present invention is another method of preparing acompound of Formula III which comprises:

(a) treating an N-alkyl piperidine 3-carboxylic acid ester with lithiumhydroxide to form the corresponding salt;

(b) reacting the salt with methyllithium to produce the corresponding3-acetyl-N-alkyl-piperidine;

(c) mixing the piperidine with thiourea and halogen to form thecorresponding thiazolamine;

(d) treating the thiazolamine with an acid anhydride to form theN-substituted acid amide; and

(e) converting the product of step c or d, if desired, to apharmaceutically acceptable acid addition salt.

A fourth aspect of the present invention is a pharmaceutical compositionwhich comprises an effective amount of a compound of structural FormulaIII above in combination with a pharmaceutically acceptable carrier.

A fifth aspect of the present invention is a method of inhibitingprolactin secretion in mammals, i.e., being useful in the treatment ofhyperprolactinaemia, galactorrhoea, amenorrhoea, menstrual disorders andimpotence, comprising administering to the mammal the above identifiedpharmaceutical composition in unit dosage form.

A sixth aspect of the present invention is a method of treatinghypertension in a mammal comprising administering to the mammal theabove identified pharmaceutical composition in unit dosage form.

A seventh aspect of the present invention is a method of treatingpsychosis, i.e., schizophrenia or drug-induced, in a mammal comprisingadministering the above identified pharmaceutical composition in unitdosage form.

A eighth aspect of the present invention is a method of treatingdisorders of the central nervous system, i.e., Parkinson's disease anddepression, in mammals comprising administering the above identifiedpharmaceutical composition in unit dosage form.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the formula ##STR2## described above, comprise the presentinvention.

The compounds include solvates and hydrates and pharmaceuticallyacceptable salts of the compounds of the above formula.

The term pharmaceutically acceptable acid addition salt is intended tomean a relatively non-toxic acid addition salt, either from inorganic ororganic acids such as, for example, hydrochloric, sulfuric, phosphoric,acetic, citric, oxalic, malonic, salicylic, malic, gluconic, fumaric,succinic, ascorbic, maleic, methanesulfonic, and the like. The salts areprepared by contacting the free base form with a sufficient amount ofthe desired acid to product a salt in the conventional manner.

The free base forms, may be regenerated by treating the salt form with abase.

The alkyl and alkenyl groups of the present invention comprise bothstraight and branched carbon chains of from one to eight carbon atoms.Representatives of such groups are methyl, ethyl, propyl, isopropyl,butyl, 3-methylbutyl, pentyl, and the like.

The aralkyl groups of the present invention comprise alkyl groups whichare both straight and branched carbon chains of from one to four carbonatoms and aryls such as phenyl or phenyl substituted by lower alkyl,lower alkoxy, lower thioalkoxy, halogen, or trifluoromethyl; aryl canalso be a heterocycle such as 2-, 3-, or 4-pyridinyl; 2-, 4-, or5-pyrimidinyl, or 2-pyrazinyl.

The present invention also includes each individual stereoisomer of thecompounds depicted by Formula III, when represents a single bond.

The preferred compounds are those of Formula III where R is hydrogen oran alkyl of from one to four carbon atoms, where R' is hydrogen orCO--R,'" where R" is an alkyl of from one to eight carbon atoms, analkenyl group of from two to eight carbon atoms, an aralkyl group or agroup of the formula --(CH₂)_(n) --O--(CH₂)_(m) --CH₃ wherein n and mare each independently zero to four and where R'" is an alkyl of fromone to four carbon atoms.

The more preferred compounds for the treatment of hypertension,inhibition of prolactin secretion, Parkinson's disease and depressionare those of Formula III where R is hydrogen, R' is hydrogen or CO--R,'"R" is an alkyl group from one to three carbon atoms or an alkenyl groupfrom two to three carbon atoms and R'" is an alkyl group from one tothree carbon atoms. The more preferred compounds for the treatment ofpsychosis, i.e., schizophrenia, are those of Formula III where R ishydrogen, R' is hydrogen or CO--R,'" R" is an alkyl or alkenyl groupfrom four to six carbon atoms and R'" is an alkyl group from one tothree carbon atoms.

Particularly valuable compounds falling within the scope of the presentinvention include the following compounds:

4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine;

4-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-2-thiazolamine;

4-(1,2,5,6-tetrahydro-1-ethyl-3-pyridinyl)-2-thiazolamine;

4-(1,2,5,6-tetrahydro-1-allyl-3-pyridinyl-2-thiazolamine;

4-(1,2,5,6-tetrahydro-1-butyl-3-pyridinyl-2-thiazolamine;

4-(1,2,5,6-tetrahydro-1-pentyl-3-pyridinyl)-2-thiazolamine;

4-(1,2,5,6-tetrahydro-1-hexyl-3-pyridinyl)-2-thiazolamine;

4-(1,2,5,6-tetrahydro-1-heptyl-3-pyridinyl)-2-thiazolamine;

4-[1,2,5,6-tetrahydro-1-(3-methylbutyl)-3-pyridinyl]- 2-thiazolamine;

4-[1,2,5,6-tetrahydro-1-(2-phenylethyl)-3-pyridinyl]-2-thiazolamine;

4-[1-(2-ethoxyethyl)-1,2,5,6-tetrahydro-3-pyridinyl]-2-thiazolamine;

N-[4-(1,2,5,6-tetrahydro-1-pentyl-3-pyridinyl)-2-thiazolyl]-acetamide;

N-[4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2thiazolyl]-acetamide;

N-methyl-4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine;

N-methyl-4-(1,2,5,6-tetrahydro-1-butyl-3-pyridinyl)-2-thiazolamine;

N-methyl-4-(1,2,5,6-tetrahydro-1-pentyl-3-pyridinyl)-2-thiazolamine;

N-methyl-N-[4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolyl]-acetamide;

N-methyl-N-]4-(1,2,5,6-tetrahydro-1-pentyl-3-pyridinyl)-2-thiazolyl]-acetamide;

4-(1-propyl-3-piperidyl)-2-thiazolamine;

N-[4-(1-propyl-3-piperidyl)-2-thiazolyl]-acetamide;

4-(1-propyl-3R-piperidyl)-2-thiazolamine; and

4-(1-propyl-3S-piperidyl)-2-thiazolamine.

The above compounds may be prepared by treating a pyridinyl-thiazolaminewith an organic halide to form the corresponding 1-substitutedpyridinium salt; the reaction is carried out in ethyl alcohol oracetonitrile and is heated at reflux for 18 to 30 hours. Then thepyridinium salt is selectively reduced to form the correspondingtetrahydropyridinylthiazolamine. This step takes place in analcohol-water mixture at -10° to +10° C. with a reducing agent. Ifdesired, one can treat this thiazolamine with an acid anhydride to forman N-substituted acid amide and then convert the product, if desired, toa pharmaceutically acceptable acid addition salt.

In the preferred reaction conditions, the thiazolamine and the organichalide are refluxed in absolute ethanol or acetonitrile for 24 hours.The preferred halides are 1-bromopropane, ethyl iodide, allyl bromide,1-bromobutane, 1-bromopentane, 1-bromohexane 1-bromoheptane,1-bromo-3-methylbutane, (2-bromoethyl)benzene, or 2-bromoethyl ethylether. One may also use an organic p-toluenesulfonate in place of theorganic halide to form the intermediate pyridinium salt.

The resulting 1-substituted pyridinium salt may be selectively reducedin a 1:1 water:methanol solution by a slow addition of excess sodiumborohydride over a period of thirty minutes. The preferred method ofpreparing the amide is by dissolving the substituted thiazolamine in anacid anhydride containing anhydrous sodium acetate. Heat this underreflux in nitrogen for three hours.

The following is the schematic procedure illustrating the process.##STR3##

The hexahydro-compounds of the instant invention may be prepared bytreating 3-acetyl-N-alkylpyridines with a thiourea, in the presence of ahalogenating agent such as bromine or iodine, to form the correspondingthiazolamines.

The reaction is carried out at 90°-110° C. for 18-30 hours. Preferablythe reactions at 100° C. for 24 hours.

The substituted thiazolamine may be converted, if desired, to anN-substituted acide amide by reaction of the thiazolamine with an acidanhydride. Preferably one uses refluxing acetic anhydride for two hoursto produce the acetamide. The following schematic procedure describesthese reactions. ##STR4##

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets, and suppositories. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders or tablet disintegrating agents; it can also be encapsulatingmaterial. In powders, the carrier is a finely divided solid which is inadmixture with the finely divided active compound. In the tablet theactive compound is mixed with carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5 to 10 toabout 70 percent of the active ingredient. Suitable solid carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, a low meltingwax, cocoa butter, and the like. The term "preparation" is intended toinclude the formulation of the active compound with encapsulatingmaterial as carrier providing a capsule in which the active component(with or without other carriers) is surrounded by carrier, which is thusin association with it. Similarly, cachets are included. Tablets,powders, cachets, and capsules can be used as solid dosage forms suitabefor oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogenously therein by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby solidify.

Liquid form preparations include solutions, suspensions, and emulsions.As an example may be mentioned water or water propylene glycol solutionsfor parenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethyleneglycol solution. Aqueous solutionssuitable for oral use can be prepared by dissolving the active componentin water and adding suitable colorants, flavors, stabilizing, andthickening agents as desired. Aqueous suspensions suitable for oral usecan be made by dispersing the finely divided active component in waterwith viscous material, i.e., natural or synthetic gums, resins,methylcellulose, sodium carboxymethylcellulose, and other well-knownsuspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions, and emulsions. These particular solid form preparations aremost conveniently provided in unit dose form and as such as used toprovide a single liquid dosage unit. Alternatively, sufficient solid maybe provided so that after conversion to liquid form, multiple individualliquid doses may be obtained by measuring predetermined volumes of theliquid form preparation as with a syringe, teaspoon, or other volumetriccontainer. When multiple liquid doses are so prepared, it is preferredto maintain the unused portion of said liquid doses at low temperature(i.e.. under refrigeration) in order to retard possible decomposition.The solid form preparations intended to be converted to liquid form maycontain, in addition to the active material, flavorants, colorants,stabilizers, buffers, artificial and natural sweeteners, dispersants,thickeners, solubilizing agents, and the like. The liquid utilized forpreparing the liquid form preparation may be water, isotonic water,ethanol, glycerine, propylene glycol, and the like, as well as mixturesthereof. Naturally, the liquid utilized will be chosen with regard tothe route of administration, for example, liquid preparations containinglarge amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of these inpackaged form.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from 1 mg to 500 mg, preferably 5 to 100 mg accordingto the particular application and the potency of the active ingredient.The compositions can, if desired, also contain other compatibletherapeutic agents.

In therapeutic use, the mammalian dosage range for a subject of 70 kgbody weight is from 1 to 1500 mg per day or preferably 25 to 750 mg perday optionally in divided portions. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The compounds of the present invention act on the dopamine systems ofthe mammalian body. Some are dopamine agonists, effective against, forexample, hyperprolactinoemia, Parkinson's disease, hypertension, sexualdisorders, and acromegaly. Others are dopamine antagonists, effective asantipsychotic agents.

The method for determining the effectiveness of the compounds of theinstant invention as dopaminergic agents is explained in Mol.Pharmacol., 1976 (12) 800 herein incorporated by reference. Table 1below sets forth the results.

                  TABLE 1                                                         ______________________________________                                        Haloperidol Receptor Binding (% inhibition at 10.sup.-6 M)                    Compound               % Inhibition                                           ______________________________________                                        III (where is double bond)                                                    R = R' = H; R" = CH.sub.3                                                                            50                                                     R = R' = H; R" = CH.sub.2 CH.sub.3                                                                   49                                                     R = R' = H; R" = (CH.sub.2).sub.2 CH.sub.3                                                           66                                                     R = R' = H; R" = (CH.sub.2).sub.3 CH.sub.3                                                           57                                                     R = R' = H; R" = (CH.sub.2).sub.4 CH.sub.3                                                           26                                                     R = R' = H; R" = (CH.sub.2).sub.5 CH.sub.3                                                           88                                                     R = R' = H; R" = (CH.sub.2).sub.6 CH.sub.3                                    R = R' = H; R" = CH.sub.2 CH═ CH.sub.2                                                           40                                                     R = R' = H; R" = (CH.sub.2).sub.2 OCH.sub.2 CH.sub.3                                                 35                                                     R = R' = H; R" = (CH.sub.2).sub.2 Ph                                                                 16                                                     R = R' = H; R" = (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                 65                                                     R = Me; R' = H; R" = (CH.sub.2).sub.2 CH.sub.3                                                       Not available                                          R = Me; R' = H; R" = (CH.sub.2).sub.3 CH.sub.3                                                       Not available                                          R = Me; R' = H; R" = (CH.sub.2).sub.4 CH.sub.3                                                       Not available                                          R = H; R' = COCH.sub.3 ; R" = (CH.sub.2).sub.2 CH.sub.3                                               0                                                     R = H; R' = COCH.sub.3 ; R" = (CH.sub.2).sub.4 CH.sub.3                                               0                                                     R = Me; R' = COCH.sub.3 ; R" = (CH.sub.2).sub.2 CH.sub.3                                             Not available                                          R = Me; R' = COCH.sub.3 ; R" = (CH.sub.2).sub.4 CH.sub.3                                             Not available                                          III (where is single bond)                                                    R = R' = H; R" = (CH.sub.2).sub.2 CH.sub.3                                                           15                                                     R = H; R' =  COCH.sub.3 ; R" = (CH.sub.2).sub.2 CH.sub.3                                              9                                                     ______________________________________                                    

The effects of representative compounds of the present invention asantipsychotic agents was established by the Mouse Activity and ScreenTest Procedure described in Pharmacol. Biochem. Behav. 1978 (8) 97,herein incorporated by reference. The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Inhibition of Locomotor Activity in Mouse                                     (ED.sub.50, mg/kg)                                                            Compound               ED.sub.50                                              ______________________________________                                        III (where is double bond)                                                    R = R' = H; R" = CH.sub.3                                                                            30                                                     R = R' = H; R" = CH.sub.2 CH.sub.3                                                                   >30                                                    R = R' = H; R" = (CH.sub.2).sub.2 CH.sub.3                                                           2.9                                                    R = R' = H; R" = (CH.sub.2).sub.3 CH.sub.3                                                           7.3                                                    R = R' = H; R" = (CH.sub.2).sub.4 CH.sub.3                                                           <10                                                    R = R' = H; R" = (CH.sub.2).sub.5 CH.sub.3                                                           >30                                                    R = R' = H; R" = (CH.sub.2).sub.6 CH.sub.3                                                           10.4                                                   R = R' = H; R" = CH.sub.2 CH═ CH.sub.2                                                           3                                                      R = R' = H; R" = (CH.sub.2).sub.2 OCH.sub.2 CH.sub.3                                                 30                                                     R = R' = H; R" =  (CH.sub.2).sub.2 Ph                                                                18.1                                                   R = R' = H; R" = (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                 8.7                                                    R = Me; R' = H; R" = (CH.sub.2).sub.2 CH.sub.3                                                       10                                                     R = Me; R' = H; R" = (CH.sub.2).sub.3 CH.sub.3                                                       Not available                                          R = Me; R' = H; R" = (CH.sub.2).sub.4 CH.sub.3                                                       <10                                                    R = H; R' = COCH.sub.3 ; R" = (CH.sub.2).sub.2 CH.sub.3                                              30                                                     R = H: R' = COCH.sub.3 ; R" = (CH.sub.2).sub.4 CH.sub.3                                              10                                                     R = Me; R' = COCH.sub.3 ; R" = (CH.sub.2).sub.2 CH.sub.3                                             39                                                     R = Me; R' = COCH.sub.3 ; R" = (CH.sub.2).sub.4 CH.sub.3                                             6.4                                                    III (where is single bond)                                                    R = R' = H; R" = (CH.sub.2).sub.2 CH.sub.3                                                           10                                                     R = H; R' =  COCH.sub.3 ; R" = (CH.sub.2).sub.2 CH.sub.3                                             30                                                     ______________________________________                                    

The methodology for testing the antihypertensive action of the compoundsof the invention is described in Am. J. Med. Sci., 1970 (259)257, hereinincorporated by reference. These experiments are considered standardtests in mammals and are indicative of utility for treatment of similardiseases in humans.

                  TABLE 3                                                         ______________________________________                                        Spontaneous Hypertensive Rat (30 mg/kg, PO)                                                  Decrease in                                                    Compound       Blood Pressure                                                                              Duration                                         ______________________________________                                         ##STR5##      20% 10-15%    1 hour up to 6 hours                              ##STR6##      12-20%        up to 10 hours                                   ______________________________________                                    

The following examples are provided to enable one skilled in the art topractice the present invention. These examples are not intended in anyway to limit the scope of the invention, but are illustrative thereof.

EXAMPLE 1 4-(1,2,5,6-Tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine

A solution of 14.16 g of 4-(3-pyridinyl)-2-thiazolamine (A. Taurins andA. Blaga, J. Heterocyclic Chemistry, 1970 (7) 1137) and 50 g of1-bromopropane in 500 ml absolute ethanol was heated at reflux for 24hours. By this time, small amounts of a salt had begun to crystallize onthe walls of the flask. The solution was concentrated to dryness on arotary evaporator, leaving 30 g of a yellow solid, mp 259°-261° C.,identified as 3-(2-amino-4-thiazolyl)-1-propylpyridinium bromide,hydrobromide.

A solution of 26 g of this salt in 300 ml water: methanol (1:1) wascooled in an ice bath and treated with 25 g of sodium borohydride, insmall portions, over a period of 30 minutes. The cold bath was thenremoved and the mixture was stirred at room temperature overnight. Themixture was concentrated to about one half of the original volume andcarefully acidified by dropwise addition of concentrated HCl. Theresulting solution was made basic with concentrated ammonium hydroxideand extracted with ethyl acetate (3×75 ml). The organic layer was driedand concentrated, leaving a yellow oil which was chromatographed onSilica gel (2% NH₄ OH in ethyl acetate) to produce 4.4 g of the titlecompound, mp 121°-123° C. (dec).

EXAMPLE 2 4-(1,2,5,6-Tetrahydro-1-methyl-3-pyridinyl)-2-thiazolamine

By using the method of Example 1, but replacing the 1-bromopropane withmethyl p-toluenesulfonate, the title compound was obtained as an oilwhich was dissolved in ether and treated with the appropriate amount ofa saturated solution of hydrogen chloride in isopropanol to produce anoverall 50% yield of its dihydrochloride, mp 272° C.

EXAMPLE 3 4-(1,2,5,6-Tetrahydro-1-ethyl-3-pyridinyl)-2-thiazolamine

By following the method of Example 1, using ethyl iodide as thealkylating agent, the title compound was produced, in 50% yield, as atan solid, mp 116°-120° C.

EXAMPLE 4 4-(1,2,5,6-Tetrahydro-1-allyl-3-pyridinyl)-2-thiazolamine

When allyl bromide is used instead of the 1-bromopropane of Example 1,the title compound can be prepared. Following flash chromatography ofthe crude reaction mixture, one recrystallization from ethyl acetate wasnecessary to obtain a 30% overall yield of the compound as a light tansolid, mp 129°-132° C.

EXAMPLE 5 4-(1,2,5,6-Tetrahydro-1-butyl-3-pyridinyl)-2-thiazolamine

By replacing the 1-bromopropane of Example 1 with 1-bromobutane, thetitle compound was prepared as a tan solid (mp 220°-2° C.) which wasconverted to its dihydrochloride (mp 239°-240° C.) by the methoddescribed in Example 2.

EXAMPLE 6 4-(1,2,5,6-Tetrahydro-1-pentyl-3-pyridinyl)-2-thiazolamine

The title compound was obtained in 56% overall yield by using1-bromopentane in the method described in Example 1. The free base was areddish oil which crystallized when triturated with a small amount ofisopropanol (mp 85°-87° C.). The dihydrobromide (mp 246°-247° C.) wasprepared by a method similar to the one described in Example 2, using asaturated solution of hydrogen bromide in isopropanol.

EXAMPLE 7 4-(1,2,5,6-Tetrahydro-1-hexyl-3-pyridinyl)-2-thiazolamine

When using 1-bromohexane in the procedure of Example 1, instead of1-bromopropane, the title compound is obtained as a red oil afterchromatography. The method of Example 2 allows the formation of thedihydrochloride monohydrate, mp 200°-202° C.

EXAMPLE 8 4-(1,2,5,6-Tetrahydro-1-heptyl-3-pyridinyl)-2-thiazolamine

Repeating the method of Example 1 with 1-bromoheptane as the alkylatingagent, followed by salt formation as described in Example 2, thedihydrochloride monohydrate of the title compound was obtained, mp191°-193° C.

EXAMPLE 94-[1,2,5,6-Tetrahydro-1-(3-methylbutyl)-3-pyridinyl]-2-thiazolamine

The method of Examples 1 and 2 was repeated, using1-bromo-3-methylbutane as the alkylating agent to produce thedihydrochloride monohydrate of the title compound, mp 204° C.

EXAMPLE 104-[1,2,5,6-Tetrahydro-1-(2-phenylethyl)-3-pyridinyl]-2thiazolamine

By using (2-bromoethyl)benzene as the alkylating agent, and employingthe methods of Examples 1 and 2, the title compound was obtained as itsdihydrochloride monohydrate, mp 209°-211° C.

EXAMPLE 114-[1-(2-Ethoxyethyl)-1,2,5,6-tetrahydro-3-pyridinyl]-2-thiazolamine

The use of 2-bromoethyl ethyl ether, instead of 1-bromopropane, in theprocedure described by Example 1 allowed the preparation of the titlecompound as an oil, which was converted into its dihydrochloride (mp225°-230° C.) by the procedure described in Example 2.

EXAMPLE 12N-[4-(1,2,5,6-Tetrahydro-1-pentyl-3-pyridinyl)-2thiazolyl]acetamide

Seven grams of the4-(1,2,5,6-tetrahydro-1-pentyl-3-pyridinyl)-2-thiazolamine obtained inExample 6 was dissolved in 100 ml of acetic anhydride with 10 g ofanhydrous sodium acetate. The solution was heated at reflux under anitrogen atmosphere for three hours. The solvent was removed on a rotaryevaporator and the residue was partitioned between 150 mldichloromethane and 150 ml 10% sodium bicarbonate solution. The organiclayer was concentrated in vacuo and the residue was chromatographed onsilica gel using 2% ammonium hydroxide in ethyl acetate as the eluent.The title compound was obtained as 4.10 g of a beige solid, mp 117°-120°C.

EXAMPLE 13N-[4-(1,2,5,6-Tetrahydro-1-propyl-3-pyridinyl)-2-thiazolyl]-acetamide

Using the procedure described in Example 12 on the4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)2-thiazolamine prepared inExample 1, the title compound was obtained as a beige solid, mp109°-112° C.

EXAMPLE 14 N-Methyl-4-(3-pyridinyl)-2-thiazolamine

3-Bromoacetylpyridine hydrobromide was prepared as described by A.Dornow, H. Machens, and K. Bruncken (Chem. Ber. 1951 (84), 147), from3-acetylpyridine, and heated in water with 1.05 equivalents ofN-methylthiourea for 30 minutes. After cooling, the solution was madebasic by addition of ammonium hydroxide andN-methyl-4-(3-pyridinyl)-2-thiazolamine was obtained as an orange solid(mp 114°-116° C.) in 70% overall yield.

EXAMPLE 15N-Methyl-4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine

The procedure described in Example 1 was repeated, using theN-methyl-4-(3-pyridinyl)-2-thiazolamine prepared in Example 14 and anexcess of 1-bromopropane as the reactants. The title compound waspurified by column chromatography (65% yield) and converted to its HClsalt by the procedure of Example 2. The resulting salt (mp 138° C.)contained 1.25 molecules of HCl and one molecule of water.

EXAMPLE 16N-methyl-4-(1,2,5,6-tetrahydro-1-pentyl-3-pyridinyl)-2-thiazolamine

The procedure of Example 1 was repeated, using theN-methyl-4-(3-pyridinyl)-2-thiazolamine prepared in Example 14 and anexcess of 1-bromopentane as the reactants. The title compound waspurified by column chromatography (53% yield) and converted to its HClsalt by the procedure of Example 2. The salt obtained (mp 168°-172° C.)contained 1.5 molecules of HCl and one molecule of water.

EXAMPLE 17N-methyl-N-[4-(1,2,5,6-tetrahydro-1-pentyl-3-pyridinyl)-2-thiazolyl[-acetamide

By applying the method of Example 12 to the compound obtained in Example16, the title compound was prepared as a tan solid, mp 78°-81° C.

EXAMPLE 18 4-(1-Propyl-3-piperidyl)-2-thiazolamine

Ethyl N-propylnipecotate (73.86 g) was dissolved in 500 ml ethanol,treated with lithium hydroxide monohydrate (15.57 g) at reflux for 24hours. Upon evaporation and drying in vacuo (100° C., eight hours),lithium N-propylnipecotate was obtained (white powder; 60 g). A solutionof 17.7 g of this salt in 200 ml THF was treated dropwise with oneequivalent of methyl-lithium, at 0° C. After stirring at roomtemperature overnight, an aqueous work-up yielded3-acetyl-N-propylpiperidine (mp of HCl salt 108°-111° C.). When 2.5 ofthis compound were intimately mixed with 2.28 g of thiourea and 3.81 gof iodine and heated on a steam bath for 24 hours, followed by a columnchromatography (Silica; acetone) and salt formation by the procedure ofExample 2, 1.75 g of 4-(1-propyl-3-piperidyl)-2-thiazolaminehydrochloride (mp 243°-248° C.) were obtained.

EXAMPLE 19 N-[4-(1-prooyl-3-piperidyl)-2-thiazolyl]acetamide4-(1-Propyl-3-piperidyl)-2-thiazolamine (1.8 g), prepared as describedin Example 18, was refluxed in 8 ml acetic anhydride for two hours. Anaqueous work-up was followed by a column chromatography (Silica;methanol) and salt formation by the procedure of Example 2.N-[4-(1-propyl-3-piperidyl)-2-thiazolyl]acetamide hydrochloride (1.3 g,mp 250°-5° C.) was obtained; this salt contained 1/4 molecule of water.

We claim:
 1. A compound having the structural formula ##STR7## wheresignifies the presence of a single or double bond between two carbonatoms; R is H or a straight or branched alkyl of from one to four carbonatoms; R' is H or a straight or branched alkyl of from one to fourcarbon atoms, R" is a straight or branched alkyl group of from one toeight carbon atoms, a straight or branched alkenyl group of from two toeight carbon atoms, an aralkyl group wherein the alkyl is straight orbranched from one to four carbon atoms, or a group of the formula--(CH₂)_(n) --O--(CH₂)_(m) --CH₃ wherein n and m are each independentlyzero to four; R'" is a straight or branched alkyl group of from one tofour carbon atoms; or the stereoisomers thereof when is a single bond,or a pharmaceutically acceptable acid addition salt thereof.
 2. Acompound according to claim 1 wherein R is H or a methyl group.
 3. Acompound according to claim 1 wherein R' is H, or a methyl group.
 4. Acompound according to claim 1 wherein R" is a straight or branched alkylof from one to eight carbon atoms.
 5. A compound according to claim 1wherein R" is a straight or branched alkenyl of from one to eight carbonatoms.
 6. A compound according to claim 1 wherein R" is an aryl-alkylwherein the alkyl is from one to four carbon atoms.
 7. A compoundaccording to claim 1 and being4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine.
 8. Acompound according to claim 1 and being4-(1,2,5,6-tetrahydro-1-allyl-3-pyridinyl)-2-thiazolamine.
 9. A compoundaccording to claim 1 and being4-(1,2,5,6-tetrahydro-1-butyl-3-pyridinyl)-2-thiazolamine.
 10. Acompound according to claim 1 and being4-(1-propyl-3-piperidyl)-2-thiazolamine.
 11. An antipsychoticpharmaceutical composition comprising an effective amount of a compoundas defined in claim 1 in combination with a pharmaceutically acceptablecarrier.
 12. A method of treating psychosis in mammals which comprisesadministering to said mammals a pharmaceutical composition in accordancewith claim 11 in unit dosage form.